Development of novel and stable glucagon formulations for closed loop systems

描述（由申请人提供）：通过响应连续感测到的葡萄糖浓度数据给药胰岛素来自动将血糖浓度维持在正常范围内的器械系统代表了机械模拟正常β细胞生理学并解决当今与强化胰岛素治疗相关的许多问题（包括改善糖尿病患者的生活质量和改善葡萄糖控制）的现代尝试。这种“闭环”人工胰腺在算法上将连续葡萄糖传感器与胰岛素输注泵连接的开发是一个活跃的研究领域。大多数使用仅使用胰岛素的实验性人工胰腺（AP）系统的研究表明，使用多种实验算法尚未消除需要碳水化合物给药的低血糖症。人工胰腺的仅胰岛素方法不能完全模拟正常生理学，因为没有通过使用反调节激素来中止即将发生的低血糖的能力。这种仅有胰岛素的AP系统对葡萄糖浓度下降作出反应的唯一方式是减少或停止输注皮下胰岛素。这不能保证胰岛素作用的迅速终止，部分原因是皮下空间中残留胰岛素。在正常生理学中，胰腺α细胞分泌胰高血糖素以对抗胰岛素的降糖作用。这些反调节激素之一是胰高血糖素，其是一种29个氨基酸的肽，其刺激储存在肝脏中的糖原转化为葡萄糖（糖原分解）。最近的闭环胰岛素研究（其中胰高血糖素也在算法上用于防止阻碍性低血糖）显示出极好的血糖控制，低血糖发生率非常低。然而，目前市售形式的胰高血糖素在溶液中是化学和物理不稳定的，因此对于双激素人工胰腺系统的临床开发是不实用的。Biodel科学家已经制备了pH 7的胰高血糖素水溶液的实验室制剂，该制剂在溶液中保持稳定。在本申请中，Biodel建议优化胰高血糖素的多种pH 7水性制剂，以在冷藏和（如果可能）室温（25 ℃）条件下提供至少18个月的稳定性，以满足长期储存要求。我们将评估所有现行美国药典（USP）药典方法是否适用于这些制剂，如果需要，我们将开发合适的方法。我们将在猪模型中证明生物活性，并将证明我们的制剂在高温下与市售胰岛素泵系统相容至少9天。 公共卫生相关性：糖尿病患者强化胰岛素治疗的全部益处在很大程度上尚未实现，因为使用当前技术来优化连续可变的胰岛素剂量要求是极其困难的，并且因为不能消除低血糖。闭环人工胰腺系统的开发是一个活跃的研究领域，有望解决第一个问题;然而，仅胰岛素系统的初步研究尚未显示出消除低血糖症。已经证明，添加算法递送的胰高血糖素作为双激素闭环系统的一部分可导致非常低的低血糖发生率。然而，目前市售的胰高血糖素制剂在高温下在化学和物理上不稳定，并且不太可能实际用于通过胰岛素泵的连续输注。在本申请中，Biodel提出了一种开发适合于连续泵输送的稳定胰高血糖素制剂的策略。

DESCRIPTION (provided by applicant): A device system which automatically maintain blood glucose concentrations in the normal range by dosing insulin in response to continuously sensed glucose concentration data represents a modern attempt to mechanically simulate normal beta cell physiology and solve many of the problems associated with intensive insulin therapy today, including improving the quality of life for patients with diabetes and improving glucose control. The development of such a "closed loop" artificial pancreas algorithmically linking continuous glucose sensors with insulin infusion pumps is an active area of research. Most studies with experimental artificial pancreas (AP) systems which have used insulin only have shown that hypoglycemia requiring carbohydrate administrations has not been eliminated using multiple experimental algorithms. The insulin- only approach to the artificial pancreas does not fully mimic normal physiology in that there is no ability to abort impending hypoglycemia through the use of counter-regulatory hormones. The only way for such insulin only AP system to react to declining glucose concentrations is to reduce or stop infusing subcutaneous insulin. This will not guarantee prompt termination of insulin effect in part because of residual depots of insulin in the subcutaneous space. In normal physiology, pancreatic alpha cells secrete glucagon to counter the glucose lowering effect of insulin. One of these counter-regulatory hormones is glucagon, a 29 amino acid peptide which stimulates the conversion of glycogen stored in the liver into glucose (glycogenolysis). Recent closed loop insulin studies in which glucagon is also used algorithmically to prevent impeding hypoglycemia have shown excellent glucose control with very low rates of hypoglycemia. Glucagon in its currently marketed form however is chemically and physically unstable in solution and therefore not practical for clinical development in bi-hormonal artificial pancreas systems. Biodel scientist have prepared lab formulations of aqueous glucagon at pH 7 that remain stable in solution. In this application, Biodel proposes to optimize multiple pH 7 aqueous formulations of glucagon to provide a minimum of 18 month stability under refrigerated and if possible, room temperature (25C) conditions for long-term storage requirements. We will assess whether all current US Pharmacopeia (USP) compendia methods are applicable to these formulations and we will develop suitable methods if required. We will demonstrate biological activity in a swine model and we will demonstrate that our formulation is compatible with a marketed insulin pump system at elevated temperatures for at least 9 days. PUBLIC HEALTH RELEVANCE: The full benefits of intensive insulin therapy for patients with diabetes have yet to be realized in large part because it is extremely difficult to optimize continuously variable insulin dose requirements using current technology and because of the inability to eliminate hypoglycemia. The development of closed loop artificial pancreas systems is an active area of research which promises to address the first problem; however initial studies of insulin-only systems have not shown elimination of hypoglycemia. The addition of algorithmically delivered glucagon as part of a bi-hormonal closed loop system has been shown to result in very low hypoglycemia rates. However, currently marketed formulations of glucagon are chemically and physically unstable at high temperatures and are not likely to be practical for continuous infusion through insulin pumps. In this application, Biodel proposes a strategy to develop a stable glucagon formulation suitable for continuous pump delivery.